The field of this invention relates to methods, compositions and articles of manufacture for preventing transmission of the human immunodeficiency virus (xe2x80x9cHIVxe2x80x9d). In a particularly preferred embodiment, the invention relates to ICAM-1 agonist/antagonists and their use to prevent the transmission of HIV across mucosal surfaces.
Several publications are referenced herein. Full citations for these publications are provided below. The disclosures of these publications are hereby incorporated herein by reference in their entirety, unless otherwise noted.
Understanding the mechanisms of viral transmission is critical for preventing the spread of HIV, the causative agent of Acquired Immune Deficiency Syndrome (AIDS). Limiting the AIDS pandemic worldwide depends, in large part, on the ability to prevent fiurther transmission and spread of HIV.
A critical feature of sexual transmission of HIV-1 is that the vaginal or mucosal surface that is initially exposed to this virus is covered with epithelial cells, which are not among the cells that are usually associated with HIV-1 infection. To cross this barrier, virus must (1) directly transverse or infect epithelial cells, (2) be associated with cells that can migrate between epithelial cells, or (3) come into contact with injectable host cells that extend between epithelial cells. Experimental evidence exists to support all of these possibilities. Previous studies suggest that epithelial cells can be productively infected, but that transmission to and from these cells requires direct interaction with infected or injectable cells.
Physical contact between latent HIV-infected leukocytes, CD4 leukocytes and epithelial cells from unrelated individuals triggers rapid assembly and release of HIV-1 into the enclosed space between donor and acceptor cells. During this process, monocytes form microvilli that intimately associate with epithelial membrane. Virions sequestered in these sites are then internalized in the epithelial cells within phagocytic endosomes. These observations, supported by abundant additional studies, demonstrate that cell-cell interaction is critical to the efficient transmission of HIV-1 to and from epithelial cells.
ICAM-1 is a single-chain glycoprotein adhesion molecule constitutively expressed on resting endothelial cells, resting monocytes, resting epithelial cells as well as activated T-cells. ICAM-1 expression is induced by a variety of cytokines including IFN-xcex3, TNFxcex1, and IL-1. The CD18 family of cellular adhesion molecules mediate interactions between cells of the immune and inflammatory system. LFA-1, also known as Lymphocyte Function-Associated Antigen-1 or CD11a/CD18, recognizes and binds to ICAM-1, ICAM-2 and ICAM-3 on the endothelium. The heterodimeric structure of LFA-1 consists of an alpha and a beta chain. As a member of the integrin family, LFA-1 plays a role in many cellular processes such as migration, antigen presentation, and cell proliferation. For example, LFA-1 mediates the binding of leukocytes to endothelial cells permitting the migration of leukocytes from the bloodstream into the tissue. ICAM-1 is the primary ligand for LFA-1. ICAM-1 is anchored to the endothelium by a transmembrane domain, has a short cytoplasmic tail, contains five extracellular immunoglobulin-like domains, and is expressed on HIV-infected monocytes and epithelial cells.
U.S. Pat. No. 5,891,841 (xe2x80x9cthe ""841 patentxe2x80x9d) is directed to methods of using intracellular adhesion molecules (ICAM-3) to suppress migration of HIV-1 infected cells from the circulatory system. According to the ""841 patent, induction of ICAM-1 on epithelial cells, endothelial cells, and fibroblasts mediates LFA-1 dependent adhesion of lymphocytes (col. 12, lines 48-50). LFA-1 and ICAM-1 are receptors for one another and are referred to in the ""841 patent as xe2x80x9creceptorxe2x80x9d and xe2x80x9cligandxe2x80x9d respectively. Id. In particular, the ""841 patent implicates the interaction between ICAM-1 and LFA-1 in the formation of HIV-induced syncytium formation. According to the ""841 patent, LFA-1 has the greatest affinity for ICAM-1 in comparison to ICAM-2 and ICAM-3 (col. 14, lines 9-16).
U.S. Pat. No. 5,674,982 (xe2x80x9cthe ""982 patentxe2x80x9d) refers to the use of anti-ICAM-1 antibodies to reduce the infectivity of rhinovirus by interfering with the interaction between LFA-1 and ICAM-1. PCT Application WO 90/13316 A1 refers to a method of suppressing the migration of HIV-1 infected cells from the circulatory system by impairing the ability of the HIV-infected leukocyte to bind to ICAM-1 or a member of the CD11/CD18 family of receptor molecules.
The role of such adhesion molecules in the transepithelial transmission of cell-associated or cell-free virus has not been addressed. Previous methods and compositions are directed to blocking the interaction of ICAM-1 and LFA-1 to prevent migration of viruses from the circulatory system at sites distant from the site of initial exposure. The role of ICAM-1, independent of its interaction with LFA-1, in viral transmission at the site of exposure to HIV or at the point of viral entry into the body, has not been addressed.
What is needed are methods and composition for blocking transepithelial transmission of HIV at the site of exposure to the virus.
This invention provides new methods, compositions, and articles of manufacture for preventing the transepithelial, transmission of HIV to an animal. Prior art methods involving ICAM-1 are directed to interfering with the ICAM-1/LFA-1 binding and preventing migration of virus from the circulatory system, across endothelial cells, into body tissue. The present invention is directed to blocking transepithelial transmission of HIV at the site of exposure to the virus, and prevents HIV infection rather than treating infection after the fact.
In a preferred embodiment, the invention provides a method of blocking transepithelial transmission of HIV at the site of exposure to the virus using an ICAM-1 agonist/antagonist. In another preferred embodiment, the blocking of viral transmission does not require blocking the binding of ICAM-1 to LFA-1. In further preferred embodiment, the invention provides a method of blocking transepithelial transmission of HIV across mucosal surfaces, e.g., genital, vaginal, rectal, oral, gastrointestinal, using a composition or article of manufacture containing an ICAM-1 agonist/antagonist. Also provided are methods of using genetically-modified bacteria capable of producing an ICAM-1 agonist/antagonist for inoculating a mucosal surface.
In another preferred embodiment, the present invention provides a pharmaceutical composition for blocking transepithelial transmission of HIV comprising an ICAM-1 agonist/antagonist and a pharmaceutically acceptable carrier. In yet another preferred embodiment, the invention provides an article of manufacture comprising an ICAM-1 agonist/antagonist and a substrate. The preferred substrates include cervical rings, condoms and intrauterine devices.
Additional embodiments and advantages of the present invention will be set forth in part in the description that follows, and in part will be obvious from the description, or may be learned through the practice of the invention. The objects and advantages of the invention will be attained by means of the instnumentalities and combinations particularly pointed out in the appended claims.